6beta, 19-seleno-1-dehydrotestosterone and esters thereof



United States Patent 63,19-SELENO-1-DEHYDROTESTOSTERONE AND ESTERSTHEREOF Klaus G. Florey, Westfield, N. J., assignor to Olin MathiesonChemical Corporation, New York, N. Y., a corporation of Virginia NoDrawing. Application September 18, 1956 Serial No. 610,641

7 Claims. (Cl. 260-4395) This application is a continuation-in-part ofmy parent application, Serial No. 547,315, filed November 16, 1955, nowabandoned.

This invention relates to the synthesis of steroids and, moreparticularly, to new selenium-containing steroid derivatives oftestosterone and to process for preparing and using them.

The new steroids of this invention comprise 6/:?,19-seleno-1-dehydrotestosterone and esters thereof.

These new steroids are prepared by heating to a temperature below 200 C.testosterone or an ester thereof [particularly a hydrocarbon carboxylicacid ester, wherein the acyl radical has less than ten carbon atoms, asexemplified by lower alkanoyl (e. g., formyl, acetyl, propionyl, butyryland enanthoyl), hydrocarbon aroyl (e. g., benzoyl and toluyl) andhydrocarbon aralkanoyl (e. g., phenylacetyl and B-phenylpropionyD], withselenium dioxide, preferably in a suitable organic solvent for thesteroid reactant, which is unattacked by selenium dioxide under thereaction conditions employed. Suitable organic solvents include ethers(e. g., dioxane), acid anhydrides (e. g., acetic anhydride), tertiaryalcohols (e. g., tertiary butanol) and preferably organic acids(especially liquid lower fatty acids, such as acetic acid). The reactionis carried out at an elevated temperature below 200 C., such as one inthe range of about 80 C. to about 140 C. (optimally at reflux of theorganic solvent, if one is used). At least one mole of selenium dioxideis required for the reaction, but preferably an excess (about 3 to 4moles) is used. If an ester of testosterone isemployed as a reactant,the corresponding ester derivative is initially formed. This ester canthen be converted to the free 17-hydroxyl compound by treatment with abase, such as methanolic potassium carbonate.

The product formed is 6,8,19-seleno-l-dehydrotestosterone (or an esterthereof) and can be represented by the structural formula 0 thereof) isheated with a pyrophoric form of nickel (e. g.,

Raney nickel). According to the other alternative pro- 2,875,196Patented Feb. 24, 1959 cedure, 6 3,19-seleno-l-dehydrotestosterone (oran ester thereof) is pyrolized by heating to a temperature of about 300C. to about 500 C. (optimally about 350 C. to about 370 C. in vacuo) toyield. l-dehydrotestosterone.

The following examples illustrate the invention:

EXAMPLE 1 6,8,19-selen0-1dehydratestosterone acetate A mixture of 2.0 g.of testosterone acetate (A -androstene-17B-ol-3-one 17-acetate) and 2.0g. of selenium dioxide in 8 ml. of acetic acid is refluxed for one hour,cooled to room temperature and filtered from selenium. The filtrate isdiluted with 50 ml. of chloroform and washed with water and sodiumbicarbonate solution. The solvent is evaporated, and theresultingresidue, upon crystallization from acetone-hexane, yields about700 mg. of a. crystalline substance, 6,3,l9-seleno-l-dehydrotestosteroneacetate, having the following properties: M. P. about l52l57 C.; [a](c., 0.62 in chloroform); A5,}; 244 in (e=7,930); 257 mu (e=7,800); 306my. (e= 889); Am" 5.76;; (acetyl), 6.10;, 6.17,, 6.27;. (A 3- keto). I

Analysis.-Calculated for C H O Se (405.38): C, 62.22; H, 6.47; Se,19.49. Found: C, 63.06; H, 7.07; Se, 17.85.

In a similar manner, upon the substitution of other esters oftestosterone (e. g., testosterone propionate and testosterone enanthate)for testosterone acetate in the procedure of Example 1, thecorresponding ester derivatives (e. g., the propionate and enanthateanalogues) are formed. Furthermore, when the process is repeated productis obtained.

6 13,1 9-seleno-1 -dehy drotestostercme To 400 mg. of6,3,19-seleno-l-dehydrotestosterone acetate in 40 ml. of ethanol wasadded 2 ml. of a 10% aqueous potassium carbonate solution. The mixtureis refluxed for 3 hours, diluted with chloroform and washed with water.Evaporation of the solvent and subsequent crystallization from methanolyields about mg. of the crystalline substance,6B,19-seleno-l-dehydrotestosterone, having the following properties: M.P. about 273-275" C.; [a] 4.6 (c., 0.54 in chloroform);

M3; 245 m (e=10,800); 257 m (e=10,700); 307 m (e=l,170); A231? 2.87;;(IT-OH), 610 6.20;, 6.28 (A "-3-keto) Analysis.Calculated for C H O Se(363.34): C,

62.80; H, 6.66; Se, 21.73. Found: C, 62.58; H, 6.76; Se,

EXAMPLE 3 l-dehydrotestosterone To 200 mg. of6,8,19-seleno-l-dehydrotestosterone in 18 ml. of benzene is added 4 ml.of Raney nickel in 4 ml. of ethanol. The mixture is refluxed for 5hours. The mixture is filtered from nickel, washed with water andconcentrated to dryness in vacuo. The residue, upon crystallization frometherhexane, yields l-dehydrotestosterone, identical with an authenticsample.

EXAMPLE 4 I-dehydrotestasterone acetate and 6-dehydrotestoster0neacetate 300 mg. of 6/8,19-seleno-l-dehydrotestosterone acetate is heatedto 350-370 C. at 1 mm. pressure for 30 minutes. The reaction mixture isdiluted with chloroform, filtered from selenium, washed with water andconcen- 7 l 3 trated'todryiie's's in vacuo: The residue ischromatographed I on alumina,- a-nd the-following portions in order ofelution are obtained with hexane-benzene and benzeneether solventmixtures: (a)"l-dehydrotestosterone acetate, M. P; 151-453 Cl, identicalwithauthenticma terial} and (1))" mixturesof l-dehydrotestosteroneacetate" and 6-dehydrotestosterone acetate, identified by'-ultraviole't'maxima in'the .240 mp.'-and 280m;w regions; 7

The invention may be otherwise variously embodied 3'..A1r=ester' of65,19-seleno-1rdehydrotestosterone with a' hydrocarbon carboxylic acidofle'ss than ten carbon atoms;

4. 619,19-s'e1eno 1 dehydrotestosterone acetate. 7

'5'. A process for preparing a compoundselected'frorn the groupconsistingof 6/8,19 selenoq dehydrotestosteron and esters thereof" withhydrocarbon carboxylic acids of'less-than ten carbon atoms, whichcomprises heat to temperature below 200 selenium dioitide and a steroidselected from the 'group consisting-of testosterone and esters oftestosterone with hydrocarbon carboxylic acids of less than ten carbonatoms, at least one mole of selenium dioxide being present per mole ofsteroid, and recovering the product thus formed.

6. The process of claim 5, wherein the steroid is an ester of"testosterone with a hydrocarbon-carboriylid ac-id of less than tencarbon atoms.

7., The process of claim 5, wherein the steroid is testoev steroneacetate;

References Cited in the file of thisp'atent UNITED sT-ArEs-PA'rENTs 12,422,904 Inhoflen Iune 24, 1947 2,695,286 Dearborn' Nov. 23, 19542,705,237 Djerassi Mar. 29, 1955 2,729,634 Dearborn- Jan. 3, 1956 OTHERREFERENCES Chem. Reviews .by Watkins, vol. 36 (1945)', 'page:249'.Schwenk: Arch Biochem. 1'4, (1947').

McKenzie: J3 Biol. Chem. 173, 271 (1947').

1. A COMPOUND SELECTED FROM THE GROUP COMSISTING OF6B,19-SELENO-1-DEHYDROTESTOSTERONE AND ESTERS THEREOF WITH HYDROCARBONCARBOXYLIC ACIDS OF LESS THAN TEN CARBON ATOMS.